ClinVar Genomic variation as it relates to human health
NM_000020.3(ACVRL1):c.140G>C (p.Arg47Pro)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000020.3(ACVRL1):c.140G>C (p.Arg47Pro)
Variation ID: 381525 Accession: VCV000381525.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q13.13 12: 51913177 (GRCh38) [ NCBI UCSC ] 12: 52306961 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Mar 8, 2017 Feb 14, 2024 Jan 3, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000020.3:c.140G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000011.2:p.Arg47Pro missense NM_001077401.2:c.140G>C NP_001070869.1:p.Arg47Pro missense NC_000012.12:g.51913177G>C NC_000012.11:g.52306961G>C NG_009549.1:g.10760G>C LRG_543:g.10760G>C LRG_543t1:c.140G>C LRG_543p1:p.Arg47Pro - Protein change
- R47P
- Other names
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- Canonical SPDI
- NC_000012.12:51913176:G:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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ACVRL1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
985 | - |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
criteria provided, single submitter
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Jun 9, 2022 | RCV000426666.4 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 3, 2024 | RCV002272232.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 10, 2016 | RCV002392977.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(May 25, 2020)
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criteria provided, single submitter
Method: clinical testing
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Telangiectasia, hereditary hemorrhagic, type 2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002558028.1
First in ClinVar: Aug 08, 2022 Last updated: Aug 08, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease … (more)
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0104 - Dominant Negative is a mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from arginine to proline (exon 3). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0309 - Alternative amino acid changes at the same position have been observed in gnomAD (5 heterozygotes, 0 homozygotes). (N) 0502 - Missense variant with conflicting in-silico predictions and/or uninformative conservation. (N) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0802 - Moderate previous evidence of pathogenicity in unrelated individuals. The variant has previously been described as pathogenic in patients with hereditary haemorrhagic telangiectasia (PMID: 16542389, 16470589, 22991266, 26176610), however it has also been classified as a VUS (ClinVar). (P) 0902 - Moderate evidence for segregation with disease. The variant has been shown to segregate with disease in six affected individuals from one family (PMID: 16470589). (P) 1002 - Moderate functional evidence supporting abnormal protein function. Functional studies in transfected cells showed that the variant resulted in a non-functional protein (PMID: 26176610). (P) 1101 - Very strong and specific phenotype match. (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign (less)
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Likely pathogenic
(Oct 10, 2016)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002701748.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.R47P variant (also known as c.140G>C), located in coding exon 2 of the ACVRL1 gene, results from a G to C substitution at nucleotide … (more)
The p.R47P variant (also known as c.140G>C), located in coding exon 2 of the ACVRL1 gene, results from a G to C substitution at nucleotide position 140. The arginine at codon 47 is replaced by proline, an amino acid with dissimilar properties. This variant was described in a Spanish family in which the proband had a clinical diagnosis of hereditary hemorrhagic telangiectasia (HHT), including cerebral and hepatic arteriovenous malformations; the alteration was also detected in five other family members with epistaxis and telangiectasias (Fernandez-L A et al. Hum. Mutat., 2006 Mar;27:295). Kinetic and thermodynamic study indicates that this variant causes protein misfolding and aggregation which leads to defective binding to BMP9 in the ALK1 signaling pathway (Townson et al 2012, J. Biol. Chem., 287:27313-27325). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jun 09, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000520849.5
First in ClinVar: Mar 08, 2017 Last updated: Mar 04, 2023 |
Comment:
Reported in multiple unrelated individuals with features of HHT in published literature, including one family where the variant was found in five relatives with epistaxis … (more)
Reported in multiple unrelated individuals with features of HHT in published literature, including one family where the variant was found in five relatives with epistaxis and telangiectasias and one relative with hepatic and cerebral arteriovenous malformations (Fernandez et al., 2006; Wehner et al., 2006; Nishida et al., 2012); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22028876, 22991266, 26176610, 16542389, 16470589) (less)
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Pathogenic
(Jan 03, 2024)
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criteria provided, single submitter
Method: clinical testing
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Telangiectasia, hereditary hemorrhagic, type 2
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV003441097.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 47 of the ACVRL1 protein (p.Arg47Pro). … (more)
This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 47 of the ACVRL1 protein (p.Arg47Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary hemorrhagic telangiectasia (PMID: 16470589, 16542389, 22991266, 26176610). ClinVar contains an entry for this variant (Variation ID: 381525). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ACVRL1 protein function. Experimental studies have shown that this missense change affects ACVRL1 function (PMID: 26176610). For these reasons, this variant has been classified as Pathogenic. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Functional and splicing defect analysis of 23 ACVRL1 mutations in a cohort of patients affected by Hereditary Hemorrhagic Telangiectasia. | Alaa El Din F | PloS one | 2015 | PMID: 26176610 |
Brain arteriovenous malformations associated with hereditary hemorrhagic telangiectasia: gene-phenotype correlations. | Nishida T | American journal of medical genetics. Part A | 2012 | PMID: 22991266 |
Specificity and structure of a high affinity activin receptor-like kinase 1 (ALK1) signaling complex. | Townson SA | The Journal of biological chemistry | 2012 | PMID: 22718755 |
Mutation analysis in hereditary haemorrhagic telangiectasia in Germany reveals 11 novel ENG and 12 novel ACVRL1/ALK1 mutations. | Wehner LE | Clinical genetics | 2006 | PMID: 16542389 |
Mutation study of Spanish patients with hereditary hemorrhagic telangiectasia and expression analysis of Endoglin and ALK1. | Fernandez-L A | Human mutation | 2006 | PMID: 16470589 |
Text-mined citations for rs774389618 ...
HelpRecord last updated Feb 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.